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Indoxyl sulfate (IS) is an accumulative protein-bound uremic toxin found in patients with kidney disease. It is reported that IS impairs the vascular endothelium, but a comprehensive overview of all mechanisms active in IS-injury currently remains lacking. Here we performed RNA sequencing in human umbilical vein endothelial cells (HUVECs) after IS or control medium treatment and identified 1293 genes that were affected in a IS-induced response. Gene enrichment analysis highlighted pathways involved in altered vascular formation and cell metabolism. We confirmed these transcriptome profiles at the functional level by demonstrating decreased viability and increased cell senescence in response to IS treatment. In line with the additional pathways highlighted by the transcriptome analysis, we further could demonstrate that IS exposure of HUVECs promoted tubule formation as shown by the increase in total tubule length in a 3D HUVECs/pericytes co-culture assay. Notably, the pro-angiogenic response of IS and increased ROS production were abolished when CYP1B1, one of the main target genes that was highly upregulated by IS, was silenced. This observation indicates IS-induced ROS in endothelial cells is CYP1B1-dependent. Taken together, our findings demonstrate that IS promotes angiogenesis and CYP1B1 is an important factor in IS-activated angiogenic response.
Jiayi Pei; Rio Juni; Magdalena Harakalova; Dirk J. Duncker; Folkert W. Asselbergs; Pieter Koolwijk; Victor Van Hinsbergh; Marianne C. Verhaar; Michal Mokry; Caroline Cheng; Pei; Juni; Hinsbergh. Indoxyl Sulfate Stimulates Angiogenesis by Regulating Reactive Oxygen Species Production via CYP1B1. Toxins 2019, 11, 454 .
AMA StyleJiayi Pei, Rio Juni, Magdalena Harakalova, Dirk J. Duncker, Folkert W. Asselbergs, Pieter Koolwijk, Victor Van Hinsbergh, Marianne C. Verhaar, Michal Mokry, Caroline Cheng, Pei, Juni, Hinsbergh. Indoxyl Sulfate Stimulates Angiogenesis by Regulating Reactive Oxygen Species Production via CYP1B1. Toxins. 2019; 11 (8):454.
Chicago/Turabian StyleJiayi Pei; Rio Juni; Magdalena Harakalova; Dirk J. Duncker; Folkert W. Asselbergs; Pieter Koolwijk; Victor Van Hinsbergh; Marianne C. Verhaar; Michal Mokry; Caroline Cheng; Pei; Juni; Hinsbergh. 2019. "Indoxyl Sulfate Stimulates Angiogenesis by Regulating Reactive Oxygen Species Production via CYP1B1." Toxins 11, no. 8: 454.
In pulmonary arterial hypertension (PAH), lung-angioproliferation leads to increased pulmonary vascular resistance, while simultaneous myocardial microvessel loss contributes to right ventricular (RV) failure. Endothelial colony forming cells (ECFC) are highly proliferative, angiogenic cells that may contribute to either pulmonary vascular obstruction or to RV microvascular adaptation. We hypothesize ECFC phenotypes (outgrowth, proliferation, tube formation) are related to markers of disease severity in a prospective cohort-study of 33 PAH and 30 healthy subjects. ECFC were transplanted in pulmonary trunk banded rats with RV failure. The presence of ECFC outgrowth in PAH patients was associated with low RV ejection fraction, low central venous saturation and a shorter time to clinical worsening (5.4 months (0.6–29.2) vs. 36.5 months (7.4–63.4), p = 0.032). Functionally, PAH ECFC had higher proliferative rates compared to control in vitro, although inter-patient variability was high. ECFC proliferation was inversely related to RV end diastolic volume (R2 = 0.39, p = 0.018), but not pulmonary vascular resistance. Tube formation-ability was similar among donors. Normal and highly proliferative PAH ECFC were transplanted in pulmonary trunk banded rats. While no effect on hemodynamic measurements was observed, RV vascular density was restored. In conclusion, we found that ECFC outgrowth associates with high clinical severity in PAH, suggesting recruitment. Transplantation of highly proliferative ECFC restored myocardial vascular density in pulmonary trunk banded rats, while RV functional improvements were not observed.
Josien Smits; Dimitar Tasev; Stine Andersen; Robert Szulcek; Liza Botros; Steffen Ringgaard; Asger Andersen; Anton Vonk-Noordegraaf; Pieter Koolwijk; Harm Jan Bogaard. Blood Outgrowth and Proliferation of Endothelial Colony Forming Cells are Related to Markers of Disease Severity in Patients with Pulmonary Arterial Hypertension. International Journal of Molecular Sciences 2018, 19, 3763 .
AMA StyleJosien Smits, Dimitar Tasev, Stine Andersen, Robert Szulcek, Liza Botros, Steffen Ringgaard, Asger Andersen, Anton Vonk-Noordegraaf, Pieter Koolwijk, Harm Jan Bogaard. Blood Outgrowth and Proliferation of Endothelial Colony Forming Cells are Related to Markers of Disease Severity in Patients with Pulmonary Arterial Hypertension. International Journal of Molecular Sciences. 2018; 19 (12):3763.
Chicago/Turabian StyleJosien Smits; Dimitar Tasev; Stine Andersen; Robert Szulcek; Liza Botros; Steffen Ringgaard; Asger Andersen; Anton Vonk-Noordegraaf; Pieter Koolwijk; Harm Jan Bogaard. 2018. "Blood Outgrowth and Proliferation of Endothelial Colony Forming Cells are Related to Markers of Disease Severity in Patients with Pulmonary Arterial Hypertension." International Journal of Molecular Sciences 19, no. 12: 3763.
Pulmonary arterial hypertension (PAH) is associated with angioproliferation in the lung and, paradoxically, vascular rarefaction in the right ventricle (RV). Endothelial colony forming cells (ECFC) are angioproliferative endothelial cells implicated in tissue repair. Here we investigated wether ECFC characteristics correlate with disease severity, pulmonary vascular resistance (PVR) and RV-function. Methods: ECFC were collected from 36 PAH and 21 healthy donors. Proliferation and angiogenic capacity upon GF stimulation were analyzed. Subsequently, in vitro findings correlated to clinical parameters including PVR, time to clinical worsening (TTCW), mixed venous oxygen saturation (SvO2), RV volumes and ejection fraction (RVEF). In addition, we investigated the effect of PAH ECFC infusion in pulmonary trunk banded rats. Results: ECFCs could be obtained from two thirds of PAH donors. Presence of ECFC outgrowth was associated with a worse clinical profile (RVEF p=0.05, SvO2 p=0.05, TTCW p=0.05). In addition, the number of colonies correlated negatively with SvO2 (R2=0.35, p=0.01). On the contrary, a low proliferative speed of PAH ECFCs was associated with RV dilatation. Transplantation of proliferative, angiogenic PAH ECFC in rats subjected to pulmonary trunk banding, improved vascular density of RV-cardiac tissue, but was not associated with improved RV function. Conclusion: These data suggest circulating ECFC are upregulated in end-stage disease and play a compensatory role in the pressure overloaded RV by improving cardiac muscle vascularity.
Josien Smits; Dimitar Tasev; Robert Szulcek; Stine Andersen; Steffen Ringaard; Janus Hyldebradt; Asgar Andersen; Anton Vonk-Noordegraaf; Pieter Koolwijk; Harm-Jan Bogaard. Outgrowth, proliferative speed and angiogenic capacity of Endothelial Colony Forming Cells (ECFC) correlate with disease severity and right ventricular (RV) adaptation in Pulmonary Arterial Hypertension (PAH) patients. Pulmonary hypertension 2018, 52, PA3934 .
AMA StyleJosien Smits, Dimitar Tasev, Robert Szulcek, Stine Andersen, Steffen Ringaard, Janus Hyldebradt, Asgar Andersen, Anton Vonk-Noordegraaf, Pieter Koolwijk, Harm-Jan Bogaard. Outgrowth, proliferative speed and angiogenic capacity of Endothelial Colony Forming Cells (ECFC) correlate with disease severity and right ventricular (RV) adaptation in Pulmonary Arterial Hypertension (PAH) patients. Pulmonary hypertension. 2018; 52 ():PA3934.
Chicago/Turabian StyleJosien Smits; Dimitar Tasev; Robert Szulcek; Stine Andersen; Steffen Ringaard; Janus Hyldebradt; Asgar Andersen; Anton Vonk-Noordegraaf; Pieter Koolwijk; Harm-Jan Bogaard. 2018. "Outgrowth, proliferative speed and angiogenic capacity of Endothelial Colony Forming Cells (ECFC) correlate with disease severity and right ventricular (RV) adaptation in Pulmonary Arterial Hypertension (PAH) patients." Pulmonary hypertension 52, no. : PA3934.
Pulmonary arterial hypertension (PAH) is associated with increased levels of circulating growth factors and corresponding receptors, such as PDGF, FGF and VEGF. Nintedanib, a tyrosine kinase inhibitor targeting primarily these receptors, is approved for the treatment of patients with idiopathic pulmonary fibrosis. Our objective was to examine the effect of nintedanib on proliferation of human pulmonary microvascular endothelial cells (MVEC) and assess its effects in rats with advanced experimental pulmonary hypertension (PH). Proliferation was assessed in control and PAH MVEC exposed to nintedanib. PH was induced in rats by subcutaneous injection of Sugen (SU5416) and subsequent exposure to 10% hypoxia for 4 weeks (SuHx model). Four weeks after re-exposure to normoxia, nintedanib was administered once daily for three weeks. Effects of the treatment were assessed with echocardiography, right heart catheterization and histological analysis of the heart and lungs. Changes in extracellular matrix production was assessed in human cardiac fibroblasts stimulated with nintedanib. Decreased proliferation with nintedanib was observed in control MVEC, but not in PAH patient derived MVEC. Nintedanib treatment did not affect right ventricular systolic pressure or total pulmonary resistance index in SuHx rats and had no effects on pulmonary vascular remodeling. However, despite unaltered pressure overload, the right ventricle showed less dilatation and decreased fibrosis, hypertrophy and collagen type III with nintedanib treatment. This could be explained by less fibronectin production by cardiac fibroblasts exposed to nintedanib. Nintedanib inhibits proliferation of pulmonary MVECs from controls, but not from PAH patients. While in rats with experimental PH nintedanib has no effects on the pulmonary vascular pathology, it has favorable effects on right ventricular remodeling.
Nina Rol; Michiel A De Raaf; Xiaoqing Q Sun; Vincent P Kuiper; Denielli Da Silva Gonçalves Bos; Chris Happé; Kondababu Kurakula; Chris Dickhoff; Raphael Thuillet; Ly Tu; Christophe Guignabert; Ingrid Schalij; Kirsten Lodder; Xiaoke Pan; Franziska E Herrmann; Geerten P Van Nieuw Amerongen; Pieter Koolwijk; Anton Vonk-Noordegraaf; Frances S De Man; Lutz Wollin; Marie-José Goumans; Robert Szulcek; Harm J Bogaard. Nintedanib improves cardiac fibrosis but leaves pulmonary vascular remodelling unaltered in experimental pulmonary hypertension. Cardiovascular Research 2018, 115, 432 -439.
AMA StyleNina Rol, Michiel A De Raaf, Xiaoqing Q Sun, Vincent P Kuiper, Denielli Da Silva Gonçalves Bos, Chris Happé, Kondababu Kurakula, Chris Dickhoff, Raphael Thuillet, Ly Tu, Christophe Guignabert, Ingrid Schalij, Kirsten Lodder, Xiaoke Pan, Franziska E Herrmann, Geerten P Van Nieuw Amerongen, Pieter Koolwijk, Anton Vonk-Noordegraaf, Frances S De Man, Lutz Wollin, Marie-José Goumans, Robert Szulcek, Harm J Bogaard. Nintedanib improves cardiac fibrosis but leaves pulmonary vascular remodelling unaltered in experimental pulmonary hypertension. Cardiovascular Research. 2018; 115 (2):432-439.
Chicago/Turabian StyleNina Rol; Michiel A De Raaf; Xiaoqing Q Sun; Vincent P Kuiper; Denielli Da Silva Gonçalves Bos; Chris Happé; Kondababu Kurakula; Chris Dickhoff; Raphael Thuillet; Ly Tu; Christophe Guignabert; Ingrid Schalij; Kirsten Lodder; Xiaoke Pan; Franziska E Herrmann; Geerten P Van Nieuw Amerongen; Pieter Koolwijk; Anton Vonk-Noordegraaf; Frances S De Man; Lutz Wollin; Marie-José Goumans; Robert Szulcek; Harm J Bogaard. 2018. "Nintedanib improves cardiac fibrosis but leaves pulmonary vascular remodelling unaltered in experimental pulmonary hypertension." Cardiovascular Research 115, no. 2: 432-439.
Elevated plasma total homocysteine (tHcy) is associated with increased risk of cardiovascular disease, but the mechanisms underlying this association are not completely understood. Cellular hypomethylation has been suggested to be a key pathophysiologic mechanism, since S-adenosylhomocysteine (AdoHcy), the Hcy metabolic precursor and a potent inhibitor of methyltransferase activity, accumulates in the setting of hyperhomocysteinemia. In this study, the impact of folate and methionine on intracellular AdoHcy levels and protein arginine methylation status was studied. Human endothelial cells were incubated with increasing concentrations of folinic acid (FnA), a stable precursor of folate, with or without methionine restriction. The levels of intracellular AdoHcy and AdoMet, tHcy in the cell culture medium, and protein-incorporated methylarginines were evaluated by suitable liquid chromatography techniques. FnA supplementation, with or without methionine restriction, reduced the level of tHcy and did not affect intracellular AdoMet levels. Interestingly, FnA supplementation reduced intracellular AdoHcy levels only in cells grown under methionine restriction. Furthermore, these cells also displayed increased protein arginine methylation status. These observations suggest that folic acid supplementation may enhance cellular methylation capacity under a low methionine status. Our results lead us to hypothesize that the putative benefits of folic acid supplementation in restoring endothelial homeostasis, thus preventing atherothrombotic events, should be reevaluated in subjects under a methionine restriction diet.
Ruben Esse; Tom Teerlink; Pieter Koolwijk; Isabel Tavares De Almeida; Henk J. Blom; Rita Castro. Folinic Acid Increases Protein Arginine Methylation in Human Endothelial Cells. Nutrients 2018, 10, 404 .
AMA StyleRuben Esse, Tom Teerlink, Pieter Koolwijk, Isabel Tavares De Almeida, Henk J. Blom, Rita Castro. Folinic Acid Increases Protein Arginine Methylation in Human Endothelial Cells. Nutrients. 2018; 10 (4):404.
Chicago/Turabian StyleRuben Esse; Tom Teerlink; Pieter Koolwijk; Isabel Tavares De Almeida; Henk J. Blom; Rita Castro. 2018. "Folinic Acid Increases Protein Arginine Methylation in Human Endothelial Cells." Nutrients 10, no. 4: 404.
Chronic hypoxia is associated with muscle wasting and decreased oxidative capacity. By contrast, training under hypoxia may enhance hypertrophy and increase oxidative capacity as well as oxygen transport to the mitochondria, by increasing myoglobin (Mb) expression. The latter may be a feasible strategy to prevent atrophy under hypoxia and enhance an eventual hypertrophic response to anabolic stimulation. Mb expression may be further enhanced by lipid supplementation. We investigated individual and combined effects of hypoxia, insulin-like growth factor (IGF)-1 and lipids, in mouse skeletal muscle C2C12 myotubes. Differentiated C2C12 myotubes were cultured for 24 h under 20%, 5% and 2% oxygen with or without IGF-1 and/or lipid treatment. In culture under 20% oxygen, IGF-1 induced 51% hypertrophy. Hypertrophy was only 32% under 5% and abrogated under 2% oxygen. This was not explained by changes in expression of genes involved in contractile protein synthesis or degradation, suggesting a reduced rate of translation rather than of transcription. Myoglobin mRNA expression increased by 75% under 5% O2 but decreased by 50% upon IGF-1 treatment under 20% O2, compared to control. Inhibition of mammalian target of rapamycin (mTOR) activation using rapamycin restored Mb mRNA expression to control levels. Lipid supplementation had no effect on Mb gene expression. Thus, IGF-1-induced anabolic signaling can be a strategy to improve muscle size under mild hypoxia, but lowers Mb gene expression.
Eva L. Peters; Sandra M. Van Der Linde; Ilse S. P. Vogel; Mohammad Haroon; Carla Offringa; Gerard M. J. De Wit; Pieter Koolwijk; Willem J. Van Der Laarse; Richard T. Jaspers. IGF-1 Attenuates Hypoxia-Induced Atrophy but Inhibits Myoglobin Expression in C2C12 Skeletal Muscle Myotubes. International Journal of Molecular Sciences 2017, 18, 1889 .
AMA StyleEva L. Peters, Sandra M. Van Der Linde, Ilse S. P. Vogel, Mohammad Haroon, Carla Offringa, Gerard M. J. De Wit, Pieter Koolwijk, Willem J. Van Der Laarse, Richard T. Jaspers. IGF-1 Attenuates Hypoxia-Induced Atrophy but Inhibits Myoglobin Expression in C2C12 Skeletal Muscle Myotubes. International Journal of Molecular Sciences. 2017; 18 (9):1889.
Chicago/Turabian StyleEva L. Peters; Sandra M. Van Der Linde; Ilse S. P. Vogel; Mohammad Haroon; Carla Offringa; Gerard M. J. De Wit; Pieter Koolwijk; Willem J. Van Der Laarse; Richard T. Jaspers. 2017. "IGF-1 Attenuates Hypoxia-Induced Atrophy but Inhibits Myoglobin Expression in C2C12 Skeletal Muscle Myotubes." International Journal of Molecular Sciences 18, no. 9: 1889.
During prolonged hypoxic conditions, endothelial cells change their gene expression to adjust to the low oxygen environment. This process is mainly regulated by the hypoxia-inducible factors, HIF-1α and HIF-2α. Although endothelial cells do not form sprouts during prolonged hypoxic culturing, silencing of HIF-2α partially restores sprout formation. The present study identifies novel HIF-2α-target genes that may regulate endothelial sprouting during prolonged hypoxia. The gene expression profile of primary human microvascular endothelial cells (hMVECs) that were cultured at 20 % oxygen was compared to hMVECs that were cultured at 1 % oxygen for 14 days by using genome-wide RNA-sequencing. The differentially regulated genes in hypoxia were compared to the genes that were differentially regulated upon silencing of HIF-2α in hypoxia. Surprisingly, KEGG pathway analysis showed that metabolic pathways were enriched within genes upregulated in response to hypoxia and enriched within genes downregulated upon HIF-2α silencing. Moreover, 51 HIF-2α-regulated genes were screened for their role in endothelial sprouting in hypoxia, of which four genes ARRDC3, MME, PPARG and RALGPS2 directly influenced endothelial sprouting during prolonged hypoxic culturing. The manipulation of specific downstream targets of HIF-2α provides a new, but to be further evaluated, perspective for restoring reduced neovascularization in several pathological conditions, such as diabetic ulcers or other chronic wounds, for improvement of vascularization of implanted tissue-engineered scaffolds.
Tessa D. Nauta; Marloes Van Den Broek; Sue Gibbs; Tineke C. T. M. Van Der Pouw-Kraan; Cees B. Oudejans; Victor W. M. Van Hinsbergh; Pieter Koolwijk. Identification of HIF-2α-regulated genes that play a role in human microvascular endothelial sprouting during prolonged hypoxia in vitro. Angiogenesis 2016, 20, 39 -54.
AMA StyleTessa D. Nauta, Marloes Van Den Broek, Sue Gibbs, Tineke C. T. M. Van Der Pouw-Kraan, Cees B. Oudejans, Victor W. M. Van Hinsbergh, Pieter Koolwijk. Identification of HIF-2α-regulated genes that play a role in human microvascular endothelial sprouting during prolonged hypoxia in vitro. Angiogenesis. 2016; 20 (1):39-54.
Chicago/Turabian StyleTessa D. Nauta; Marloes Van Den Broek; Sue Gibbs; Tineke C. T. M. Van Der Pouw-Kraan; Cees B. Oudejans; Victor W. M. Van Hinsbergh; Pieter Koolwijk. 2016. "Identification of HIF-2α-regulated genes that play a role in human microvascular endothelial sprouting during prolonged hypoxia in vitro." Angiogenesis 20, no. 1: 39-54.
Purpose of review Tissue regeneration requires proper vascularization. In vivo studies identified that the endothelial-colony forming cells (ECFCs), a subtype of endothelial progenitor cells that can be isolated from umbilical cord or peripheral blood, represent a promising cell source for therapeutical neovascularization. ECFCs not only are able to initiate and facilitate neovascularization in diseased tissue but can, by acting in paracrine manner, contribute to the creation of favorable conditions for efficient and appropriate differentiation of tissue-resident stem or progenitor cells. This review outlines the progress in the field of in vivo regenerative and tissue engineering studies and surveys why, when and how ECFCs can be used for tissue regeneration. Recent findings Reviewed literature that regards human derived ECFCs in xenogeneic animal models implicates that ECFCs should be considered as an endothelial cell source of preference for induction of neovascularization. Their neovascularization and regenerative potential is augmented in combination with other types of stem or progenitor cells. Biocompatible scaffolds pre-vascularized with ECFCs interconnect faster and better with the host vasculature. The physical incorporation of ECFCs in newly-formed blood vessels grants prolonged release of trophic factors of interest, which also makes ECFCs an interesting cell source candidate for gene therapy and delivery of bioactive compounds in targeted area. Summary ECFCs possess all biological features to be considered as a cell source of preference for tissue engineering and repair of blood supply. Investigation of regenerative potential of ECFCs in autologous settings in large animal models prior to clinical application is the next step to clearly outline the most efficient strategy for using ECFCs as treatment.
Dimitar Tasev; Pieter Koolwijk; Victor W.M. Van Hinsbergh. Therapeutic Potential of Human-Derived Endothelial Colony-Forming Cells in Animal Models. Tissue Engineering Part B: Reviews 2016, 22, 371 -382.
AMA StyleDimitar Tasev, Pieter Koolwijk, Victor W.M. Van Hinsbergh. Therapeutic Potential of Human-Derived Endothelial Colony-Forming Cells in Animal Models. Tissue Engineering Part B: Reviews. 2016; 22 (5):371-382.
Chicago/Turabian StyleDimitar Tasev; Pieter Koolwijk; Victor W.M. Van Hinsbergh. 2016. "Therapeutic Potential of Human-Derived Endothelial Colony-Forming Cells in Animal Models." Tissue Engineering Part B: Reviews 22, no. 5: 371-382.
Introduction: Fibrin-matrices of different stiffness can be used for tissue engineering. The differentiation and extracellular matrix (ECM) remodeling properties of mesenchymal stem cells can be influenced by matrix stiffness. We hypothesized that stiffer fibrin matrices slow matrix degradation and favor the osteogenic differentiation of human adipose-derived stem cells (hASCs). Materials and Methods: hASCs were incorporated at different densities into soft and stiff fibrin matrices composed of 2 mg/ml fibrinogen and 0.1 or 1.0 IU/ml thrombin. The Young's moduli of the matrices were determined by nano-indentation. Fibrin degradation was determined during a 14 day culture period by ELISA. qPCR and histology were used to assess ECM remodeling and osteogenic differentiation. Results: Fibrin matrices polymerized with 1.0 IU/ml thrombin were 69% stiffer than those polymerized with 0.1 IU/ml. Stiffer matrices degraded more than soft matrices. Higher cell seeding densities increased matrix degradation. Cells in stiffer matrices produced more Alkaline Phosphatase and ECM than cells in softer matrices. RUNX-2 expression was almost ten times higher in stiff matrices than in soft matrices. Discussion: Only stiff fibrin matrices induced osteogenic differentiation of hASCs. Unexpectedly, this was accompanied by enhanced cell-mediated matrix remodeling. These results suggest that a mechanical threshold for differentiation and ECM-remodeling was reached for cells embedded in the stiff matrices.
Thijs De Jong; Ester M. Weijers; Astrid D. Bakker; Pieter Koolwijk; Theo H. Smit. Matrix Remodeling and Osteogenic Differentiation of Human Adipose-Derived Stem Cells Increases with Higher Fibrin Matrix Stiffness. Journal of Biomaterials and Tissue Engineering 2016, 6, 729 -738.
AMA StyleThijs De Jong, Ester M. Weijers, Astrid D. Bakker, Pieter Koolwijk, Theo H. Smit. Matrix Remodeling and Osteogenic Differentiation of Human Adipose-Derived Stem Cells Increases with Higher Fibrin Matrix Stiffness. Journal of Biomaterials and Tissue Engineering. 2016; 6 (9):729-738.
Chicago/Turabian StyleThijs De Jong; Ester M. Weijers; Astrid D. Bakker; Pieter Koolwijk; Theo H. Smit. 2016. "Matrix Remodeling and Osteogenic Differentiation of Human Adipose-Derived Stem Cells Increases with Higher Fibrin Matrix Stiffness." Journal of Biomaterials and Tissue Engineering 6, no. 9: 729-738.
During short-term hypoxia, Hypoxia Inducible Factors (particular their subunits HIF-1α and HIF-2α) regulate the expression of many genes including the potent angiogenesis stimulator VEGF. However, in some pathological conditions chronic hypoxia occurs and is accompanied by reduced angiogenesis. We investigated the effect of prolonged hypoxia on the proliferation and sprouting ability of human microvascular endothelial cells and the involvement of the HIFs and Dll4/Notch signaling. Human microvascular endothelial cells (hMVECs), cultured at 20% oxygen for 14 days and seeded on top of 3D fibrin matrices, formed sprouts when stimulated with VEGF-A/TNFα. In contrast, hMVECs precultured at 1% oxygen for 14 days were viable and proliferative, but did not form sprouts into fibrin upon VEGF-A/TNFα stimulation at 1% oxygen. Silencing of HIF-2α with si-RNA partially restored the inhibition of endothelial sprouting, whereas HIF-1α or HIF-3α by si-RNA had no effect. No involvement of Dll4/Notch pathway in the inhibitory effect on endothelial sprouting by prolonged hypoxia was found. In addition, hypoxia decreased the production of urokinase-type plasminogen activator (uPA), needed for migration and invasion, without a significant effect on its inhibitor PAI-1. This was independent of HIF-2α, as si-HIF-2α did not counteract uPA reduction. Prolonged culturing of hMVECs at 1% oxygen inhibited endothelial sprouting into fibrin. Two independent mechanisms contribute. Silencing of HIF-2α with si-RNA partially restored the inhibition of endothelial sprouting pointing to a HIF-2α-dependent mechanism. In addition, reduction of uPA contributed to reduced endothelial tube formation in a fibrin matrix during prolonged hypoxia.
Tessa D. Nauta; Monique C. A. Duyndam; Ester M. Weijers; Victor M. W. Van Hinsbergh; Pieter Koolwijk. HIF-2α Expression Regulates Sprout Formation into 3D Fibrin Matrices in Prolonged Hypoxia in Human Microvascular Endothelial Cells. PLOS ONE 2016, 11, e0160700 .
AMA StyleTessa D. Nauta, Monique C. A. Duyndam, Ester M. Weijers, Victor M. W. Van Hinsbergh, Pieter Koolwijk. HIF-2α Expression Regulates Sprout Formation into 3D Fibrin Matrices in Prolonged Hypoxia in Human Microvascular Endothelial Cells. PLOS ONE. 2016; 11 (8):e0160700.
Chicago/Turabian StyleTessa D. Nauta; Monique C. A. Duyndam; Ester M. Weijers; Victor M. W. Van Hinsbergh; Pieter Koolwijk. 2016. "HIF-2α Expression Regulates Sprout Formation into 3D Fibrin Matrices in Prolonged Hypoxia in Human Microvascular Endothelial Cells." PLOS ONE 11, no. 8: e0160700.
Vascular endothelial growth factor A (VEGF-A) is a key molecule in angiogenesis acting through VEGF receptors (VEGFRs), ανβ3 integrin, receptor protein tyrosine phosphatase beta/zeta (RPTPβ/ζ) and cell surface nucleolin (NCL). Pleiotrophin (PTN) stimulates endothelial cell migration and limits the angiogenic effects of VEGF-A165 to the levels of its own effect, possibly acting as a VEGF-A165 modifier. Since PTN and VEGF-A165 share receptors and actions on endothelial cells, in the present work we studied whether and how VEGF-A165 affects PTN expression or secretion. VEGF-A165 decreased PTN mRNA and protein levels acting at the transcriptional level. Bevacizumab, a selective VEGFR2 tyrosine kinase inhibitor and down-regulation of VEGFR2 expression by siRNA did not affect this decrease, suggesting that it is VEGFR-independent. VEGF-A121 also decreased PTN mRNA and protein levels, suggesting that heparin binding of VEGF-A165 is not involved. Blockage of cell surface NCL, lack of expression or mutation of β3 integrin and down-regulation of RPTPβ/ζ abolished the inhibitory effect of VEGF-A165 on PTN expression and secretion. Down-regulation of endogenous PTN in endothelial cells enhanced VEGF-A165-induced increase in migration and tube formation on matrigel. Collectively, these data suggest that VEGF-A down-regulates PTN expression and secretion through the RPTPβ/ζ-ανβ3-NCL axis to enhance its own effect on cell migration and further highlight the role of RPTPβ/ζ in VEGF-A actions.
Evangelia Poimenidi; Christina Theodoropoulou; Marina Koutsioumpa; Lamprini Skondra; Eirini Droggiti; Marloes Van Den Broek; Pieter Koolwijk; Evangelia Papadimitriou. Vascular endothelial growth factor A (VEGF-A) decreases expression and secretion of pleiotrophin in a VEGF receptor-independent manner. Vascular Pharmacology 2016, 80, 11 -19.
AMA StyleEvangelia Poimenidi, Christina Theodoropoulou, Marina Koutsioumpa, Lamprini Skondra, Eirini Droggiti, Marloes Van Den Broek, Pieter Koolwijk, Evangelia Papadimitriou. Vascular endothelial growth factor A (VEGF-A) decreases expression and secretion of pleiotrophin in a VEGF receptor-independent manner. Vascular Pharmacology. 2016; 80 ():11-19.
Chicago/Turabian StyleEvangelia Poimenidi; Christina Theodoropoulou; Marina Koutsioumpa; Lamprini Skondra; Eirini Droggiti; Marloes Van Den Broek; Pieter Koolwijk; Evangelia Papadimitriou. 2016. "Vascular endothelial growth factor A (VEGF-A) decreases expression and secretion of pleiotrophin in a VEGF receptor-independent manner." Vascular Pharmacology 80, no. : 11-19.
Endothelial colony-forming cells (ECFC) are grown from circulating CD34+ progenitors present in adult peripheral blood, but during in vitro expansion part of the cells lose CD34. To evaluate whether the regulation of CD34 characterizes the angiogenic phenotypical features of PB-ECFCs, we investigated the properties of CD34+ and CD34− ECFCs with respect to their ability to form capillary-like tubes in 3D fibrin matrices, tip-cell gene expression, and barrier integrity. Selection of CD34+ and CD34− ECFCs from subcultured ECFCs was accomplished by magnetic sorting (FACS: CD34+: 95 % pos; CD34−: 99 % neg). Both fractions proliferated at same rate, while CD34+ ECFCs exhibited higher tube-forming capacity and tip-cell gene expression than CD34− cells. However, during cell culture CD34− cells re-expressed CD34. Cell-seeding density, cell–cell contact formation, and serum supplements modulated CD34 expression. CD34 expression in ECFCs was strongly suppressed by newborn calf serum. Stimulation with FGF-2, VEGF, or HGF prepared in medium supplemented with 3 % albumin did not change CD34 mRNA or surface expression. Silencing of CD34 with siRNA resulted in strengthening of cell–cell contacts and increased barrier function of ECFC monolayers as measured by ECIS. Furthermore, CD34 siRNA reduced tube formation by ECFC, but did not affect tip-cell gene expression. These findings demonstrate that CD34+ and CD34− cells are different phenotypes of similar cells and that CD34 (1) can be regulated in ECFC; (2) is positively involved in capillary-like sprout formation; (3) is associated but not causally related to tip-cell gene expression; and (4) can affect endothelial barrier function.
Dimitar Tasev; Lara S. F. Konijnenberg; Joana Amado-Azevedo; Michiel H. Van Wijhe; Pieter Koolwijk; Victor W. M. Van Hinsbergh. CD34 expression modulates tube-forming capacity and barrier properties of peripheral blood-derived endothelial colony-forming cells (ECFCs). Angiogenesis 2016, 19, 325 -338.
AMA StyleDimitar Tasev, Lara S. F. Konijnenberg, Joana Amado-Azevedo, Michiel H. Van Wijhe, Pieter Koolwijk, Victor W. M. Van Hinsbergh. CD34 expression modulates tube-forming capacity and barrier properties of peripheral blood-derived endothelial colony-forming cells (ECFCs). Angiogenesis. 2016; 19 (3):325-338.
Chicago/Turabian StyleDimitar Tasev; Lara S. F. Konijnenberg; Joana Amado-Azevedo; Michiel H. Van Wijhe; Pieter Koolwijk; Victor W. M. Van Hinsbergh. 2016. "CD34 expression modulates tube-forming capacity and barrier properties of peripheral blood-derived endothelial colony-forming cells (ECFCs)." Angiogenesis 19, no. 3: 325-338.
A defect in neo-vascularization process involving circulating angiogenic mononuclear cells (CACs) dysfunction is associated with diabetes. We showed that oxidative stress was elevated in CACs cultured from blood of individuals with metabolic syndrome (MetS) and diabetes. We then assessed the action of palmitic acid (PA), a deregulated and increased NEFA in metabolic disorders, focusing on its oxidant potential. We observed that the phyto-polyphenol resveratrol normalized oxidative stress both in CACs isolated from MetS patients or treated with PA. Resveratrol further decreased the deleterious action of PA on gene expression of vascularization factors (TNFα, VEGF-A, SDF1α, PECAM-1, VEGFR2, Tie2 and CXCR4) and improved CAC motility. Particularly, resveratrol abolished the PA-induced over-expression of the pro-oxidant protein p66Shc. Neither KLF2 nor SIRT1, previously shown in resveratrol and p66Shc action, was directly involved. Silencing p66Shc normalized PA action on VEGF-A and TNFα specifically, without abolishing the PA-induced oxidative stress, which suggests a deleterious role of p66Shc independently of any major modulation of the cellular oxidative status in a high NEFA levels context. Besides showing that resveratrol reverses PA-induced harmful effects on human CAC function, certainly through profound cellular modifications, we establish p66Shc as a major therapeutic target in metabolic disorders, independent from glycemic control.
Julie Favre; Cansu Yıldırım; Thomas A. Leyen; Weena J.Y. Chen; Renate E. Van Genugten; Larissa W. Van Golen; Juan-Jesús García-Vallejo; Rene Musters; Josefien Baggen; Ruud Fontijn; Tineke Van Der Pouw Kraan; Erik Serne; Pieter Koolwijk; Michaela Diamant; Anton J.G. Horrevoets; Cansu Yildirim. Palmitic acid increases pro-oxidant adaptor protein p66Shc expression and affects vascularization factors in angiogenic mononuclear cells: Action of resveratrol. Vascular Pharmacology 2015, 75, 7 -18.
AMA StyleJulie Favre, Cansu Yıldırım, Thomas A. Leyen, Weena J.Y. Chen, Renate E. Van Genugten, Larissa W. Van Golen, Juan-Jesús García-Vallejo, Rene Musters, Josefien Baggen, Ruud Fontijn, Tineke Van Der Pouw Kraan, Erik Serne, Pieter Koolwijk, Michaela Diamant, Anton J.G. Horrevoets, Cansu Yildirim. Palmitic acid increases pro-oxidant adaptor protein p66Shc expression and affects vascularization factors in angiogenic mononuclear cells: Action of resveratrol. Vascular Pharmacology. 2015; 75 ():7-18.
Chicago/Turabian StyleJulie Favre; Cansu Yıldırım; Thomas A. Leyen; Weena J.Y. Chen; Renate E. Van Genugten; Larissa W. Van Golen; Juan-Jesús García-Vallejo; Rene Musters; Josefien Baggen; Ruud Fontijn; Tineke Van Der Pouw Kraan; Erik Serne; Pieter Koolwijk; Michaela Diamant; Anton J.G. Horrevoets; Cansu Yildirim. 2015. "Palmitic acid increases pro-oxidant adaptor protein p66Shc expression and affects vascularization factors in angiogenic mononuclear cells: Action of resveratrol." Vascular Pharmacology 75, no. : 7-18.
Circulating angiogenic cells (CACs) are monocyte-derived cells with endothelial characteristics, which contribute to both angiogenesis and arteriogenesis in a paracrine way. Interferon-β (IFN-β) is known to inhibit these divergent processes in animals and patients. We hypothesized that IFN-β might act by affecting the differentiation and function of CACs. CACs were cultured from peripheral blood mononuclear cells and phenotypically characterized by surface expression of monocytic and endothelial markers. IFN-β significantly reduced the number of CACs by 18–64%. Apoptosis was not induced by IFN-β, neither in mononuclear cells during differentiation, nor after maturation to CACs. Rather, IFN-β impaired adhesion to, and spreading on, fibronectin, which was dependent on α5β1 (VLA-5)-integrin. IFN-β affected the function of VLA-5 in mature CACs, leading to rounding and detachment of cells, by induction of calpain 1 activity. Cell rounding and detachment was completely reversed by inhibition of calpain 1 activity in mature CACs. During in vitro capillary formation, CAC addition and calpain 1 inhibition enhanced sprouting of endothelial cells to a comparable extent, but were not sufficient to rescue tube formation in the presence of IFN-β. We show that the IFN-β-induced reduction of the numbers of in vitro differentiated CACs is based on activation of calpain 1, resulting in an attenuated adhesion to extracellular matrix proteins via VLA-5. In vivo, this could lead to inhibition of vessel formation due to reduction of the locally recruited CAC numbers and their paracrine angiogenic factors.
Cansu Yıldırım; Julie Favre; Ester M. Weijers; Ruud D. Fontijn; Michiel H. Van Wijhe; Sandra J. Van Vliet; Reinier Boon; Pieter Koolwijk; Tineke C. T. M. Van Der Pouw Kraan; Anton J. G. Horrevoets. IFN-β affects the angiogenic potential of circulating angiogenic cells by activating calpain 1. American Journal of Physiology-Heart and Circulatory Physiology 2015, 309, H1667 -H1678.
AMA StyleCansu Yıldırım, Julie Favre, Ester M. Weijers, Ruud D. Fontijn, Michiel H. Van Wijhe, Sandra J. Van Vliet, Reinier Boon, Pieter Koolwijk, Tineke C. T. M. Van Der Pouw Kraan, Anton J. G. Horrevoets. IFN-β affects the angiogenic potential of circulating angiogenic cells by activating calpain 1. American Journal of Physiology-Heart and Circulatory Physiology. 2015; 309 (10):H1667-H1678.
Chicago/Turabian StyleCansu Yıldırım; Julie Favre; Ester M. Weijers; Ruud D. Fontijn; Michiel H. Van Wijhe; Sandra J. Van Vliet; Reinier Boon; Pieter Koolwijk; Tineke C. T. M. Van Der Pouw Kraan; Anton J. G. Horrevoets. 2015. "IFN-β affects the angiogenic potential of circulating angiogenic cells by activating calpain 1." American Journal of Physiology-Heart and Circulatory Physiology 309, no. 10: H1667-H1678.
In Pulmonary Arterial Hypertension (PAH) structural and functional abnormalities in the lung lead to an increased pulmonary vascular resistance and right heart failure. Dysfunction of the pressure-regulating endothelial cells (ECs) is thought to play an crucial role. Recently it was shown in our laboratory that lung biopsy derived microvascular ECs (MVECs) from PAH-patients are unable to align under 120h of high shear stress. As the availability of these cells is limited, a suitable alternative is needed. Our aim was to investigate ECFC as a substitute for MVECs regarding reaction to shear stress. ECFC are circulating ECs, easily obtainable from venous blood.ECFCs obtained form patients expressed EC markers CD31, VE-cadherin, VEGFR2, VWF, and were negative for α-SMA, CD14, CD45. For flow experiments, an unidirectional flow (25 dyn/cm2) was applied to ECFC for 120 hours. Allignment was quantified with phase contrast microscopy. When >50% of cells aligned, this is called aligned.After 120 h 6 out of 6 control donors aligned, in the PAH group 4 out of 6 alligned. In addition we analyzed proliferation under flow. After 120 h, in the control group we count 37.25x10 cells/ cm2, in the PAH group 73,7x10/ cm2 cells (multiple t-test, corrected by Holm Sidak method) p= 0.013551.In conclusion we show that out of ECFC from 8 PAH patients 4 donors are unable to align after 120h of high fluid flow induced shear stress. This is in line with with previous observations in PAH-MVECS. In addition we found that ECFC proliferate under flow. This makes it likely that ECFC play a role in disease progression, and strengthens the hypothesis for an intrinsic base for EC dysfunction in PAH.
Josien Smits; Harm-Jan Bogaard; Pieter Koolwijk; Anton Vonk Noordegraaf. ECFCs from patients with PAH show a disturbed reaction to high fluid flow induced shear stress. Pulmonary Circulation and Pulmonary Vascular Disease 2015, 46, 1 .
AMA StyleJosien Smits, Harm-Jan Bogaard, Pieter Koolwijk, Anton Vonk Noordegraaf. ECFCs from patients with PAH show a disturbed reaction to high fluid flow induced shear stress. Pulmonary Circulation and Pulmonary Vascular Disease. 2015; 46 ():1.
Chicago/Turabian StyleJosien Smits; Harm-Jan Bogaard; Pieter Koolwijk; Anton Vonk Noordegraaf. 2015. "ECFCs from patients with PAH show a disturbed reaction to high fluid flow induced shear stress." Pulmonary Circulation and Pulmonary Vascular Disease 46, no. : 1.
Efficient implementation of peripheral blood-derived endothelial-colony cells (PB-ECFCs) as a therapeutical tool requires isolation and generation of a sufficient number of cells in ex vivo conditions devoid of animal-derived products. At present, little is known how the isolation and expansion procedure in xenogeneic-free conditions affects the therapeutical capacity of PB-ECFCs. The findings presented in this study indicate that human platelet lysate (PL) as a serum substitute yields twice more colonies per mL blood compared to the conventional isolation with fetal bovine serum (FBS). Isolated ECFCs displayed a higher proliferative ability in PL supplemented medium than cells in FBS medium during 30 days expansion. The cells at 18 cumulative population doubling levels (CPDL) retained their proliferative capacity, showed higher sprouting ability in fibrin matrices upon stimulation with FGF-2 and VEGF-A than the cells at 6 CPDL, and displayed low β-galactosidase activity. The increased sprouting of PB-ECFCs at 18 CPDL was accompanied by an intrinsic activation of the uPA/uPAR fibrinolytic system. Induced deficiency of uPA (urokinase-type plasminogen activator) or uPAR (uPA receptor) by siRNA technology completely abolished the angiogenic ability of PB-ECFCs in fibrin matrices. During the serial expansion, the gene induction of the markers associated with inflammatory activation such as VCAM-1 and ICAM-1 did not occur or only to limited extent. While further propagation up to 31 CPDL proceeded at a comparable rate, a marked upregulation of inflammatory markers occurred in all donors accompanied by a further increase of uPA/uPAR gene induction. The observed induction of inflammatory genes at later stages of long-term propagation of PB-ECFCs underpins the necessity to determine the right time-point for harvesting of sufficient number of cells with preserved therapeutical potential. The presented isolation method and subsequent cell expansion in platelet lysate supplemented culture medium permits suitable large-scale propagation of PB-ECFC. For optimal use of PB-ECFCs in clinical settings, our data suggest that 15–20 CPDL is the most adequate maturation stage.
Dimitar Tasev; Michiel H. Van Wijhe; Ester M. Weijers; Victor W. M. Van Hinsbergh; Pieter Koolwijk. Long-Term Expansion in Platelet Lysate Increases Growth of Peripheral Blood-Derived Endothelial-Colony Forming Cells and Their Growth Factor-Induced Sprouting Capacity. PLoS ONE 2015, 10, e0129935 .
AMA StyleDimitar Tasev, Michiel H. Van Wijhe, Ester M. Weijers, Victor W. M. Van Hinsbergh, Pieter Koolwijk. Long-Term Expansion in Platelet Lysate Increases Growth of Peripheral Blood-Derived Endothelial-Colony Forming Cells and Their Growth Factor-Induced Sprouting Capacity. PLoS ONE. 2015; 10 (6):e0129935.
Chicago/Turabian StyleDimitar Tasev; Michiel H. Van Wijhe; Ester M. Weijers; Victor W. M. Van Hinsbergh; Pieter Koolwijk. 2015. "Long-Term Expansion in Platelet Lysate Increases Growth of Peripheral Blood-Derived Endothelial-Colony Forming Cells and Their Growth Factor-Induced Sprouting Capacity." PLoS ONE 10, no. 6: e0129935.
Adipose tissue-derived stromal cells (ASC) form a rich source of autologous cells for use in regenerative medicine. In vitro induction of an endothelial phenotype may improve performance of ASCs in cardiovascular repair. Here, we report on an in vitro strategy using direct reprogramming of ASCs by means of ectopic expression of the endothelial-specific transcription factor SRY (sex determining region Y)-box18 (SOX18). SOX18 induces ASCs to express a set of genes involved in vascular patterning: MMP7, KDR, EFNB2, SEMA3G and CXCR4. Accordingly, SOX18 transduced ASCs reorganize under conditions of shear stress, display VEGF-induced chemotaxis and form tubular structures in 3D matrices in an MMP7-dependent manner. These in vitro findings provide insight into molecular and cellular processes downstream of SOX18 and show that reprogramming using SOX18 is sufficient to induce several endothelial-like features in ASCs.
R.D. Fontijn; J. Favre; B.A. Naaijkens; E. Meinster; N.J. Paauw; S.L. Ragghoe; T.D. Nauta; M.A. Van Den Broek; E.M. Weijers; H.W. Niessen; P. Koolwijk; A.J. Horrevoets. Adipose tissue-derived stromal cells acquire endothelial-like features upon reprogramming with SOX18. Stem Cell Research 2014, 13, 367 -378.
AMA StyleR.D. Fontijn, J. Favre, B.A. Naaijkens, E. Meinster, N.J. Paauw, S.L. Ragghoe, T.D. Nauta, M.A. Van Den Broek, E.M. Weijers, H.W. Niessen, P. Koolwijk, A.J. Horrevoets. Adipose tissue-derived stromal cells acquire endothelial-like features upon reprogramming with SOX18. Stem Cell Research. 2014; 13 (3):367-378.
Chicago/Turabian StyleR.D. Fontijn; J. Favre; B.A. Naaijkens; E. Meinster; N.J. Paauw; S.L. Ragghoe; T.D. Nauta; M.A. Van Den Broek; E.M. Weijers; H.W. Niessen; P. Koolwijk; A.J. Horrevoets. 2014. "Adipose tissue-derived stromal cells acquire endothelial-like features upon reprogramming with SOX18." Stem Cell Research 13, no. 3: 367-378.
In patients with chronic wounds, autologous tissue repair is often not sufficient to heal the wound. These patients might benefit from regenerative medicine or the implantation of a tissue-engineered scaffold. Both wound healing and tissue engineering is dependent on the formation of a microvascular network. This process is highly regulated by hypoxia and the transcription factors hypoxia-inducible factors-1α (HIF-1α) and -2α (HIF-2α). Even though much is known about the function of HIF-1α in wound healing, knowledge about the function of HIF-2α in wound healing is lacking. This review focuses on the function of HIF-1α and HIF-2α in microvascular network formation, wound healing, and therapy strategies.
Tessa D. Nauta; Victor W. M. Van Hinsbergh; Pieter Koolwijk. Hypoxic Signaling During Tissue Repair and Regenerative Medicine. International Journal of Molecular Sciences 2014, 15, 19791 -19815.
AMA StyleTessa D. Nauta, Victor W. M. Van Hinsbergh, Pieter Koolwijk. Hypoxic Signaling During Tissue Repair and Regenerative Medicine. International Journal of Molecular Sciences. 2014; 15 (11):19791-19815.
Chicago/Turabian StyleTessa D. Nauta; Victor W. M. Van Hinsbergh; Pieter Koolwijk. 2014. "Hypoxic Signaling During Tissue Repair and Regenerative Medicine." International Journal of Molecular Sciences 15, no. 11: 19791-19815.
Metallothioneins (MTs) are small cysteine-rich proteins which are involved in e.g. metal homeostasis, metal detoxification and protection against oxidative stress. In addition, several MTs have been shown to regulate expression of proangiogenic growth factors like vascular endothelial growth factor. Detailed information about the expression and regulation of specific MT isoforms in endothelial cells (EC) is limited. We therefore performed extensive mRNA expression profiling of all known human MTs in EC. We found that the basal endothelial expression is restricted to MT1E, MT1X, MT2A, and MT3. Physiological activation of EC by exposure to serum increased the expression of MT1E and MT2A and induced the expression of MT1M. Furthermore, exposure to zinc or copper induced the expression of most MT1 isoforms, while hypoxia specifically increased the expression of MT1E, MT1M, MT1X, and MT3. Finally, knockdown of the dominant MT isoform in EC, i.e. MT2A, resulted in decreased proliferation and sprouting as well as in increased migration of human umbilical vein EC. Together, these findings provide a link between MTs and angiogenesis.
Iris A. Schulkens; Kitty C.M. Castricum; Ester M. Weijers; Pieter Koolwijk; Arjan W. Griffioen; Victor Thijssen. Expression, Regulation and Function of Human Metallothioneins in Endothelial Cells. Journal of Vascular Research 2014, 51, 231 -238.
AMA StyleIris A. Schulkens, Kitty C.M. Castricum, Ester M. Weijers, Pieter Koolwijk, Arjan W. Griffioen, Victor Thijssen. Expression, Regulation and Function of Human Metallothioneins in Endothelial Cells. Journal of Vascular Research. 2014; 51 (3):231-238.
Chicago/Turabian StyleIris A. Schulkens; Kitty C.M. Castricum; Ester M. Weijers; Pieter Koolwijk; Arjan W. Griffioen; Victor Thijssen. 2014. "Expression, Regulation and Function of Human Metallothioneins in Endothelial Cells." Journal of Vascular Research 51, no. 3: 231-238.
Combined with in vitro and in vivo experiments, mathematical and computational modeling are key to unraveling how mechanical and chemical signaling by endothelial cells coordinates their organization into capillary-like tubes. While in vitro and in vivo experiments can unveil the effects of, for example, environmental changes or gene knockouts, computational models provide a way to formalize and understand the mechanisms underlying these observations. This chapter reviews recent computational approaches to model angiogenesis, and discusses the insights they provide into the mechanisms of angiogenesis. We introduce a new cell-based computational model of an in vitro assay of angiogenic sprouting from endothelial monolayers in fibrin matrices. Endothelial cells are modeled by the Cellular Potts Model, combined with continuum descriptions to model haptotaxis and proteolysis of the extracellular matrix. The computational model demonstrates how a variety of cellular structural properties and behaviors determine the dynamics of tube formation. We aim to extend this model to a multi-scale model in the sense that cells, extracellular matrix and cell-regulation are described at different levels of detail and feedback on each other. Finally we discuss how computational modeling, combined with in vitro and in vivo modeling steers experiments, and how it generates new experimental hypotheses and insights on the mechanics of angiogenesis.
Sonja E. M. Boas; Margriet M. Palm; Pieter Koolwijk; Roeland M. H. Merks. Computational Modeling of Angiogenesis: Towards a Multi-Scale Understanding of Cell–Cell and Cell–Matrix Interactions. Regenerative Strategies for the Treatment of Knee Joint Disabilities 2012, 161 -183.
AMA StyleSonja E. M. Boas, Margriet M. Palm, Pieter Koolwijk, Roeland M. H. Merks. Computational Modeling of Angiogenesis: Towards a Multi-Scale Understanding of Cell–Cell and Cell–Matrix Interactions. Regenerative Strategies for the Treatment of Knee Joint Disabilities. 2012; ():161-183.
Chicago/Turabian StyleSonja E. M. Boas; Margriet M. Palm; Pieter Koolwijk; Roeland M. H. Merks. 2012. "Computational Modeling of Angiogenesis: Towards a Multi-Scale Understanding of Cell–Cell and Cell–Matrix Interactions." Regenerative Strategies for the Treatment of Knee Joint Disabilities , no. : 161-183.